Nuclear receptors are transcription regulators that respond to various stimuli such as physiological factors (e.g., development and differentiation), environmental factors and the like, and regulate gene expression in a ligand dependent manner. They form a gene superfamily based on their structural characteristics. Among them are included classic nuclear receptors such as estrogen receptor (ER) with estrogen as a ligand, and the like, and orphan nuclear receptors whose ligands and physiological functions are unknown.
Estrogen-related receptor-α (ERR-α, NR3B1) belongs to the estrogen-related receptor subfamily (ERR subfamily) (orphan nuclear receptor closely related to ER). ERR-β and ERR-γ have additionally been identified as the members of the ERR subfamily, and all the members show high homology with ER in the DNA-binding domain. ER and the ERR subfamily are known to have common target genes such as estrogen-responsive genes and the like.
Crosstalks occur between the signal transduction pathways of ER and the ERR subfamily (non-patent documents 1 to 4). Therefore, a compound capable of modulating the activity of ERR-α (ERR-α modulator) could provide a therapeutic effect for both the diseases related to ERR-α and the diseases related to ER, through a direct modulation of the ERR-α transcriptional effect or an indirect effect on the ER signal transduction pathway.
In consideration of the wide activity of ERR-α, an ERR-α modulator is expected to be useful for the prophylaxis or treatment of various disease conditions (e.g., cancers such as to breast cancer and the like, diabetes, hyperlipidemia, obesity, metabolic syndrome, arthritis, atherosclerosis, rheumatoid arthritis, atopic dermatitis, osteoporosis, anxiety, depression, Parkinson's disease, Alzheimer's disease etc.) (patent documents 1 and 2, non-patent document 5).
In recent years, it has been reported that siRNA and a low-molecular-weight compound having an ERR-α inhibitory activity can provide a good antitumor effect against estrogen receptor-positive and -negative breast cancers in mouse models (non-patent documents 6 and 7).
As an ERR-α inverse agonist, patent document 3 (WO 2011/016501) discloses a compound represented by the formula:
whereinA is a group represented by the formula
whereinR1, R2 and R3 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), an acyl group, or a hydroxyl group optionally substituted by an alkyl group optionally having substituent(s);Y is —O—, —S— or —NRa— wherein Ra is a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), an acyl group, or a hydroxyl group optionally substituted by an alkyl group optionally having substituent(s);Z is ═O, ═S or ═NRb wherein Rb is a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), an acyl group, or a hydroxyl group optionally substituted by an alkyl group optionally having substituent(s);Y1 is —O—, —S— or —NRc— wherein Rc is a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), or an acyl group;Z1 is —ORd, —SRd or —NHRd wherein Rd are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), or an acyl group;R4 is a hydrogen atom or an alkyl group optionally having substituent(s);R5, R6, R7 and R8 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), an amino group optionally having substituent(s), a hydroxyl group optionally having a substituent, a thiol group optionally having a substituent, a carbamoyl group optionally having substituent(s), an alkyloxycarbonyl group optionally having substituent(s), a halogen atom, a cyano group or a nitro group;m and n are each independently an integer of 0 to 3;X is —O—, —CO—, —O—CO—, —CO—O—, —SO2—, —SO—, —S—, —SO2—O—, —NRc1—, —CO—NRc1—, —NRc1—CO—, —NRc1—CO—NRc2—, —O—CO—NRc1—, —NRc1—CO—O—, —SO2—NRc1—, —NRc1—SO2— or —NRc1—SO2—NRc2—                wherein Rc1 and Rc2 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), a heterocyclic group optionally having substituent(s), an acyl group, or a hydroxyl group optionally substituted by an alkyl group optionally having substituent(s); andR9 is an aromatic ring group optionally having substituent(s), provided that the following two compound:        
are excluded.
As an antiallergic agent and antihistamine agent, patent document 4 (JP-A-9-3067) discloses a compound represented by the formula:
whereinR1 is a hydrogen atom, a lower alkyl group, or an unsubstituted or substituted phenyl group,R2 is an unsubstituted or substituted phenyl group, a pyridyl group, or a 2-benzimidazolyl group having a lower alkyl group, a lower alkoxyalkyl group or an unsubstituted or substituted aralkyl group at N-position,m is an integer of 0 or 1,n is an integer of 0 to 3,Y is >S, >NH or >N—CH3, andZ is ═S, ═NH, ═O, ═NC(═NH)NH2, ═NCO—R3 or ═NSO2—R3 wherein R3 is a straight chain or branched lower alkyl group, a trifluoromethyl group or an aryl group.
As a phospholipase A2 inhibitory activating agent, patent document 5 (WO 1998/033797) discloses a compound represented by the formula:
whereinR1 is a hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused to a non-aromatic hydrocarbon ring or a non-aromatic heterocycle, optionally substituted aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl;Z is —S—, —SO—, —O—, —OCH2—, —CONH—, —CONHCH2—, —N(R16)— whereinR16 is a hydrogen atom, alkyl or aralkyl, or a single bond;X1 is —(CH2)q—CO— wherein q is an integer of 0 to 3, —(CH2)r-CO—N(R17)— wherein R17 is a hydrogen atom or lower alkyl and r is an integer of 0 to 3, —CH2NHSO2—, —(CH2)s—N(R18)—CO— wherein R18 is a hydrogen atom or lower alkyl and s is an integer of 0 to 3, —CH2NHCOCH2O—, —CH2N(R19)COCH═CH— wherein R19 is a hydrogen atom or lower alkyl, —CH2NHCS—, —CH2O—, —OCH2—, —CH2OCH2—, —CH2—N(R20)—CH2— wherein R20 is a hydrogen atom, lower alkyl or acyl, alkylene, alkenylene or a single bond;X2 is optionally substituted arylene, optionally substituted heteroarylene, heterocyclediyl, —C≡C— or a single bond;X3 is alkylene, alkenylene or a single bond;A, B, and E are each independently an oxygen atom or a sulfur atom;D is a hydrogen atom or hydroxy lower alkyl;Y is —(CH2)mCO—, —(CH2)mCONH—, —(CH2)mCSNH—, —(CH2)mSO2, —(CH2)mCOO—, —(CH2)nNHCO—, —(CH2)nNHSO2— or a single bond;m is an integer of 0 to 3;n is an integer of 1 to 3; andY2 is a group represented by the formula:
                wherein        R2 and R3 are both hydrogen atoms, or the one is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted 39 cycloalkyl, and the other is a hydrogen atom or a lower alkyl;        R4, R5, G ring, J ring and L ring are each independently optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or cycloalkenyl;        broken line (---) shows presence or absence of a bond; and p is an integer of 0 to 2,broken line (---) shows presence or absence of a bond; anda wavy line (˜) means that the bond of D is cis or trans relation to E,provided thatwhen the bond between the carbon atom adjacent to D and the carbon atom of the ring is a single bond, then X1 is alkylene and X2 and X3 are single bonds, andwhen X1 is —CH2O—, then Y1 is not a single bond, which is useful for the prophylaxis or treatment of inflammatory disease and the like.        
Non-patent document 8 (Chemical & Pharmaceutical Bulletin, 2009, vol. 57 (12), p. 1415-1420) discloses synthetic route for a compound having the following formula, and non-patent document 9 (Chemical & Pharmaceutical Bulletin, 2010, vol. 58 (8), p. 1123-1126) discloses antibacterial activity of the compound.
